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Oleg Kshives, MD, PhD
Surgery Department, Bagrationovsk Hospital, Kaliningrad, Russia
OBJECTIVE: 5-survival (5YS) and life span after radical surgery for esophageal cancer (EC) pa-tients (ECP)(T1-4N0-
2M0) - alive supersysems was analyzed. The importance must be stressed of using complex system analysis, artificial
intelligence (neural networks computing), simulation modeling and statistical methods in combination, because the
different approaches yield complementary pieces of prognostic information.
METHODS: We analyzed data of 563 consecutive ECP (age=56.6±8.9 years; tumor size=6±3.5 cm) radically operated
(R0) and monitored in 1975-2024 (m=419, f=144; esophagogastrectomies (EG) Garlock=289, EG Lewis=274, combined
EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium,
splenectomy=170; adenocarcinoma=323, squamous=230, mix=10; T1=131, T2=119, T3=185, T4=128; N0=285, N1=71,
N2=207; G1=161, G2=143, G3=259; early EC=112, invasive=451; only surgery=428, adjuvant chemoimmunoradiotherapy-
AT=135: 5-FU+thymalin/taktivin+radiotherapy 45-50Gy). Multivariate Cox modeling, clustering, SEPATH, Monte Carlo,
bootstrap and neural networks computing were used to determine any significant dependence.
RESULTS: Overall life span (LS) was 1915.4±2284.8 days and cumulative 5-year survival (5YS) reached 52.6%, 10
years – 46.3%, 20 years – 33.3%, 30 years – 27.5%. 193 ECP lived more than 5 years (LS=4309.1±2507.4 days), 105 ECP –
more than 10 years (LS=5860.8±2469.2 days). 228 ECP died because of EC (LS=629.8±324.1 days). AT significantly
improved 5YS (69% vs. 49.1%) (P=0.0007 by log-rank test). 5YS of ECP of upper/3 was significantly better than others
(65.3% vs.50.3%) (P=0.003). Cox modeling displayed that 5YS of ECP significantly depended on: phase transition (PT)
N0—N12 in terms of synergetics, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), T, G,
histology, age, AT, localization, prothrombin index, hemorrhage time, residual nitrogen, protein (P=0.000-0.019). Neural
networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and healthy
cells/CC (rank=1), PT N0—N12 (2), PT early-invasive EC (3), erythrocytes/CC (4), thrombocytes/CC (5); segmented
neutrophils/CC (6), stick neutrophils/CC (7), lymphocytes/CC (8), eosinophils/CC (9), monocytes/CC (10), leucocytes/CC
(11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT
N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC cell
dynamics; 9) EC characteristics; 10) tumor localization; 11) anthropometric data; 12) surgery type. Optimal diagnosis
and treatment strategies for EC are: 1) screening and early detection of EC; 2) availability of experienced
thoracoabdominal surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate
lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for ECP with
unfavorable prognosis.
Significant Factors (Number of Samples=3333) Rank Kendal Tau-A P
Tumor Size 1 -0.308 0.000
Healthy Cells/Cancer Cells 2 0.305 0.000
T1-4 3 -0.299 0.000
Erythrocytes/Cancer Cells 4 0.299 0.000
Leucocytes/Cancer Cells 5 0.290 0.000
Thrombocytes/Cancer Cells 6 0.285 0.000
Lymphocytes/Cancer Cells 7 0.281 0.000
Residual Nitrogen 8 -0.275 0.000
Segmented Neutrophils/Cancer Cells 9 0.273 0.000
Phase Transition N0---N12 10 -0.239 0.000
Hemorrhage Time 11 -0.228 0.000
Monocytes/Cancer Cells 12 0.227 0.000
Phase Transition Early---Invasive Cancer 13 -0.222 0.000
Esophageal/Cardioesophageal Cancer 14 -0.191 0.000
Operation Type 15 -0.187 0.000
Eosinophils/Cancer Cells 16 0.173 0.000
Stick Neutrophils/Cancer Cells 17 0.144 0.001
G1-3 18 -0.140 0.001
Tumor Growth 19 -0.113 0.01
Erythrocytes 20 0.100 0.01
Combined Procedure 21 0.095 0.01
Weight 22 0.092 0.01
Localization 23 0.069 0.05
Optimization of Management for Esophageal
Cancer Patients (T1-4N0-2M0)
Factors n=421 (Neural Networks) Rank Sensitivity
Healthy Cells/Cancer Cells 1 47967
Phase Transition N0---N12 2 32041
Phase Transition Early---Invasive Esophageal Cancer 3 32029
Erythrocytes/ Cancer Cells 4 21816
Thrombocytes/ Cancer Cells 5 20377
Segmented Neutrophils/ Cancer Cells 6 16849
Stick Neutrophils/ Cancer Cells 7 11869
Lymphocyes/ Cancer Cells 8 10648
Eosinophils/ Cancer Cells 9 10401
Monocytes/ Cancer Cells 10 9258
Leucocytes/ Cancer Cells 11 9196
Cox Regression, ECP=563
Parameter
Estimate
Standard
Error
Chi-
square
P value
95%
Lower CL
95%
Upper CL
Hazard
Ratio
Segmented Neutrophils (%) 0.060757 0.017913 11.50399 0.000694 0.02565 0.095867 1.062641
Hemorrhage of Blood 0.001559 0.000400 15.16684 0.000098 0.00077 0.002343 1.001560
Protein 0.020805 0.008677 5.74991 0.016489 0.00380 0.037811 1.021023
Residual Nitrogen 0.046396 0.010866 18.23261 0.000020 0.02510 0.067693 1.047490
Prothrombin Index 0.021704 0.006456 11.30163 0.000774 0.00905 0.034358 1.021942
Segmented Neutrophils (abs) -0.761788 0.204580 13.86576 0.000196 -1.16276 -0.360820 0.466831
Lymphocytes (abs) 0.546870 0.228784 5.71370 0.016833 0.09846 0.995277 1.727836
T1-4 0.418271 0.094110 19.75331 0.000009 0.23382 0.602724 1.519332
PT N0---N12 0.642382 0.161510 15.81930 0.000070 0.32583 0.958936 1.901004
Age 0.028998 0.007691 14.21475 0.000163 0.01392 0.044073 1.029423
Weight -0.034970 0.013244 6.97240 0.008278 -0.06093 -0.009013 0.965634
Histology -0.285581 0.125754 5.15725 0.023150 -0.53205 -0.039108 0.751577
G1-3 0.426268 0.091239 21.82750 0.000003 0.24744 0.605094 1.531532
Adjuvant Chemoimmunoradiotherapy -0.870165 0.190510 20.86250 0.000005 -1.24356 -0.496772 0.418882
Segmented Neutrophils (tot) 0.124208 0.040804 9.26585 0.002335 0.04423 0.204183 1.132252
Leucocytes/Cancer Cells -0.132461 0.037769 12.30035 0.000453 -0.20649 -0.058436 0.875937
Monocytes/Cancer Cells 1.046746 0.401192 6.80736 0.009078 0.26042 1.833067 2.848367
Upper/3 vs Others -0.456165 0.195540 5.44218 0.019656 -0.83942 -0.072914 0.633709
Eosinophils (abs) 0.887039 0.450614 3.87504 0.049009 0.00385 1.770226 2.427929
Cumulative Proportion Surviving (Kaplan-Meier)
P=0.000
Complete Censored
0 5 10 15 20 25 30 35 40 45 50
Time
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative
Proportion
Surviving
N0
N1-2
Cumulative Proportion Surviving (Kaplan-Meier)
P=0.000
Complete Censored
0 5 10 15 20 25 30 35 40 45 50
Years after Esophagogastrectomies
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative
Proportion
Surviving
Invasive ECP
Early ECP
Cumulative Proportion Surviving (Kaplan-Meier)
P=0.000
Complete Censored
0 5 10 15 20 25 30 35 40 45 50
Years after Esophagogastrectomies
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative
Proportion
Surviving
Cardioesophageal CP
Esophageal CP
Cumulative Proportion Surviving (Kaplan-Meier)
P=0.00375
Complete Censored
0 5 10 15 20 25 30 35 40 45 50
Years after Esophagogastrectomies
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative
Proportion
Surviving
Adjuvant Chemoradiotherapy
Surgery along
Cumulative Proportion Surviving (Kaplan-Meier)
P=0.000
Complete Censored
0 5 10 15 20 25 30 35 40 45 50
Years after Esophagogastrectomies
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative
Proportion
Surviving
Others
Upper/3
Survival Function
5YS=52.6%; 10YS=46.3%;
20YS=33.3%; 30YS=27.5%.
Complete Censored
-5 0 5 10 15 20 25 30 35 40 45
Years after Esophagogastrectomies
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative
Proportion
Surviving

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Kshivets Oleg Optimization of Management for Esophageal Cancer Patients (T1-4N0-2M0).

  • 1. Oleg Kshives, MD, PhD Surgery Department, Bagrationovsk Hospital, Kaliningrad, Russia OBJECTIVE: 5-survival (5YS) and life span after radical surgery for esophageal cancer (EC) pa-tients (ECP)(T1-4N0- 2M0) - alive supersysems was analyzed. The importance must be stressed of using complex system analysis, artificial intelligence (neural networks computing), simulation modeling and statistical methods in combination, because the different approaches yield complementary pieces of prognostic information. METHODS: We analyzed data of 563 consecutive ECP (age=56.6±8.9 years; tumor size=6±3.5 cm) radically operated (R0) and monitored in 1975-2024 (m=419, f=144; esophagogastrectomies (EG) Garlock=289, EG Lewis=274, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium, splenectomy=170; adenocarcinoma=323, squamous=230, mix=10; T1=131, T2=119, T3=185, T4=128; N0=285, N1=71, N2=207; G1=161, G2=143, G3=259; early EC=112, invasive=451; only surgery=428, adjuvant chemoimmunoradiotherapy- AT=135: 5-FU+thymalin/taktivin+radiotherapy 45-50Gy). Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence. RESULTS: Overall life span (LS) was 1915.4±2284.8 days and cumulative 5-year survival (5YS) reached 52.6%, 10 years – 46.3%, 20 years – 33.3%, 30 years – 27.5%. 193 ECP lived more than 5 years (LS=4309.1±2507.4 days), 105 ECP – more than 10 years (LS=5860.8±2469.2 days). 228 ECP died because of EC (LS=629.8±324.1 days). AT significantly improved 5YS (69% vs. 49.1%) (P=0.0007 by log-rank test). 5YS of ECP of upper/3 was significantly better than others (65.3% vs.50.3%) (P=0.003). Cox modeling displayed that 5YS of ECP significantly depended on: phase transition (PT) N0—N12 in terms of synergetics, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), T, G, histology, age, AT, localization, prothrombin index, hemorrhage time, residual nitrogen, protein (P=0.000-0.019). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and healthy cells/CC (rank=1), PT N0—N12 (2), PT early-invasive EC (3), erythrocytes/CC (4), thrombocytes/CC (5); segmented neutrophils/CC (6), stick neutrophils/CC (7), lymphocytes/CC (8), eosinophils/CC (9), monocytes/CC (10), leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0). CONCLUSIONS: 5YS of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC cell dynamics; 9) EC characteristics; 10) tumor localization; 11) anthropometric data; 12) surgery type. Optimal diagnosis and treatment strategies for EC are: 1) screening and early detection of EC; 2) availability of experienced thoracoabdominal surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for ECP with unfavorable prognosis. Significant Factors (Number of Samples=3333) Rank Kendal Tau-A P Tumor Size 1 -0.308 0.000 Healthy Cells/Cancer Cells 2 0.305 0.000 T1-4 3 -0.299 0.000 Erythrocytes/Cancer Cells 4 0.299 0.000 Leucocytes/Cancer Cells 5 0.290 0.000 Thrombocytes/Cancer Cells 6 0.285 0.000 Lymphocytes/Cancer Cells 7 0.281 0.000 Residual Nitrogen 8 -0.275 0.000 Segmented Neutrophils/Cancer Cells 9 0.273 0.000 Phase Transition N0---N12 10 -0.239 0.000 Hemorrhage Time 11 -0.228 0.000 Monocytes/Cancer Cells 12 0.227 0.000 Phase Transition Early---Invasive Cancer 13 -0.222 0.000 Esophageal/Cardioesophageal Cancer 14 -0.191 0.000 Operation Type 15 -0.187 0.000 Eosinophils/Cancer Cells 16 0.173 0.000 Stick Neutrophils/Cancer Cells 17 0.144 0.001 G1-3 18 -0.140 0.001 Tumor Growth 19 -0.113 0.01 Erythrocytes 20 0.100 0.01 Combined Procedure 21 0.095 0.01 Weight 22 0.092 0.01 Localization 23 0.069 0.05 Optimization of Management for Esophageal Cancer Patients (T1-4N0-2M0) Factors n=421 (Neural Networks) Rank Sensitivity Healthy Cells/Cancer Cells 1 47967 Phase Transition N0---N12 2 32041 Phase Transition Early---Invasive Esophageal Cancer 3 32029 Erythrocytes/ Cancer Cells 4 21816 Thrombocytes/ Cancer Cells 5 20377 Segmented Neutrophils/ Cancer Cells 6 16849 Stick Neutrophils/ Cancer Cells 7 11869 Lymphocyes/ Cancer Cells 8 10648 Eosinophils/ Cancer Cells 9 10401 Monocytes/ Cancer Cells 10 9258 Leucocytes/ Cancer Cells 11 9196 Cox Regression, ECP=563 Parameter Estimate Standard Error Chi- square P value 95% Lower CL 95% Upper CL Hazard Ratio Segmented Neutrophils (%) 0.060757 0.017913 11.50399 0.000694 0.02565 0.095867 1.062641 Hemorrhage of Blood 0.001559 0.000400 15.16684 0.000098 0.00077 0.002343 1.001560 Protein 0.020805 0.008677 5.74991 0.016489 0.00380 0.037811 1.021023 Residual Nitrogen 0.046396 0.010866 18.23261 0.000020 0.02510 0.067693 1.047490 Prothrombin Index 0.021704 0.006456 11.30163 0.000774 0.00905 0.034358 1.021942 Segmented Neutrophils (abs) -0.761788 0.204580 13.86576 0.000196 -1.16276 -0.360820 0.466831 Lymphocytes (abs) 0.546870 0.228784 5.71370 0.016833 0.09846 0.995277 1.727836 T1-4 0.418271 0.094110 19.75331 0.000009 0.23382 0.602724 1.519332 PT N0---N12 0.642382 0.161510 15.81930 0.000070 0.32583 0.958936 1.901004 Age 0.028998 0.007691 14.21475 0.000163 0.01392 0.044073 1.029423 Weight -0.034970 0.013244 6.97240 0.008278 -0.06093 -0.009013 0.965634 Histology -0.285581 0.125754 5.15725 0.023150 -0.53205 -0.039108 0.751577 G1-3 0.426268 0.091239 21.82750 0.000003 0.24744 0.605094 1.531532 Adjuvant Chemoimmunoradiotherapy -0.870165 0.190510 20.86250 0.000005 -1.24356 -0.496772 0.418882 Segmented Neutrophils (tot) 0.124208 0.040804 9.26585 0.002335 0.04423 0.204183 1.132252 Leucocytes/Cancer Cells -0.132461 0.037769 12.30035 0.000453 -0.20649 -0.058436 0.875937 Monocytes/Cancer Cells 1.046746 0.401192 6.80736 0.009078 0.26042 1.833067 2.848367 Upper/3 vs Others -0.456165 0.195540 5.44218 0.019656 -0.83942 -0.072914 0.633709 Eosinophils (abs) 0.887039 0.450614 3.87504 0.049009 0.00385 1.770226 2.427929 Cumulative Proportion Surviving (Kaplan-Meier) P=0.000 Complete Censored 0 5 10 15 20 25 30 35 40 45 50 Time 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving N0 N1-2 Cumulative Proportion Surviving (Kaplan-Meier) P=0.000 Complete Censored 0 5 10 15 20 25 30 35 40 45 50 Years after Esophagogastrectomies 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving Invasive ECP Early ECP Cumulative Proportion Surviving (Kaplan-Meier) P=0.000 Complete Censored 0 5 10 15 20 25 30 35 40 45 50 Years after Esophagogastrectomies 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving Cardioesophageal CP Esophageal CP Cumulative Proportion Surviving (Kaplan-Meier) P=0.00375 Complete Censored 0 5 10 15 20 25 30 35 40 45 50 Years after Esophagogastrectomies 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving Adjuvant Chemoradiotherapy Surgery along Cumulative Proportion Surviving (Kaplan-Meier) P=0.000 Complete Censored 0 5 10 15 20 25 30 35 40 45 50 Years after Esophagogastrectomies 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving Others Upper/3 Survival Function 5YS=52.6%; 10YS=46.3%; 20YS=33.3%; 30YS=27.5%. Complete Censored -5 0 5 10 15 20 25 30 35 40 45 Years after Esophagogastrectomies 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving